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Chemical Compound Review

Darusentan     (2S)-2-(4,6- dimethoxypyrimidin-2-yl)oxy- 3...

Synonyms: CHEMBL23261, SureCN795084, HMR-4005, henyl-, (S)-, EE-0200, ...
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Disease relevance of LU135252

  • Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels [1].
  • OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF) [2].
  • Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied [3].
  • Obesity potentiated contractions in response to angiotensin II in the aorta (from 6+/-2% to 33+/-5% KCl) but not in the carotid artery (4+/-1% to 3.6+/-1% KCl), an effect that was completely prevented with LU135252 treatment (6+/-0.4% versus 33+/-5% KCl) [4].
  • Long-term LU135252 treatment completely prevented this activation (13.3+/-0.3 versus 55+/-4 nmol/L, P<0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity [4].

High impact information on LU135252

  • Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk [5].
  • LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly [2].
  • RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96) [6].
  • ACE activity (nmol. L His-Leu. mg protein(-1)) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252, an orally active ET(A) receptor antagonist [4].
  • In the Dahl rat model, we studied the effects of a selective endothelin-subtype A (ET[A]) receptor antagonist, LU135252, on blood pressure, vascular structure, and function [7].

Chemical compound and disease context of LU135252


Biological context of LU135252


Anatomical context of LU135252

  • METHODS: Thirty male mongrel dogs surviving 180 min left anterior descending coronary artery balloon occlusion were randomised to: darusentan i.v. bolus-5 mg/kg 5 min before reperfusion-(group I); darusentan i.v. bolus+chronic oral-10 mg/kg/day-(group II); saline (group III) [17].
  • We describe a simple, sensitive, and reproducible radioreceptor assay (RRA) for LU135252, a selective antagonist of the ETA receptor, using porcine aortic smooth muscle membranes as the acceptor and 125I-endothelin-1 as the ligand [18].
  • To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6) [19].
  • Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan (group I) displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion [20].
  • Significant benefits in hemodynamic variables were found after 3 weeks only in patients receiving darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01) [21].

Associations of LU135252 with other chemical compounds


Gene context of LU135252

  • OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men [6].
  • Pulmonary clearance of 125I-ET-1 was decreased by chronic but not acute treatment with the specific ETA receptor antagonist LU135252 [27].
  • METHODS: ApoE-deficient and C57BL/6J control mice were fed for 30 weeks with normal chow or high-fat Western-type diet alone or in combination with darusentan (LU135252; 50 mg/kg/day) [28].
  • CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men [6].
  • Moreover, CA IV immunostaining was enhanced much later in the carotids, where darusentan did not cause regression of elastocalcinosis [29].

Analytical, diagnostic and therapeutic context of LU135252

  • METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35% [2].
  • CONCLUSIONS: Early administration of the ET(A) receptor antagonist darusentan does not affect the scar healing process at 6 weeks after experimental MI with reperfusion in dogs [17].
  • The practical performance of this RRA was then tested in plasma samples obtained from (a) rats after a single oral administration of LU135252, (b) from coronary-ligated rats chronically treated with LU135252, and (c) in plasma and urine samples obtained from dogs during intrarenal infusion of LU135252 [18].
  • In series 2, 5 min before cross-clamping, the treated group (n=7) received an intravenous bolus of LU135252 (5 mg/kg), whereas the control group (n=6) was given vehicle [30].
  • CONCLUSION: Treatment with the selective ET-A receptor antagonist LU135252 accelerates recovery of renal function after isogeneic renal transplantation and attenuates cellular graft infiltration [31].


  1. Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophyandGlomerulosclerosis. Barton, M., Vos, I., Shaw, S., Boer, P., D'Uscio, L.V., Gröne, H.J., Rabelink, T.J., Lattmann, T., Moreau, P., Lüscher, T.F. J. Am. Soc. Nephrol. (2000) [Pubmed]
  2. Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators. Spieker, L.E., Mitrovic, V., Noll, G., Pacher, R., Schulze, M.R., Muntwyler, J., Schalcher, C., Kiowski, W., Lüscher, T.F. J. Am. Coll. Cardiol. (2000) [Pubmed]
  3. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Barton, M., d'Uscio, L.V., Shaw, S., Meyer, P., Moreau, P., Lüscher, T.F. Hypertension (1998) [Pubmed]
  4. Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin. Barton, M., Carmona, R., Morawietz, H., d'Uscio, L.V., Goettsch, W., Hillen, H., Haudenschild, C.C., Krieger, J.E., Münter, K., Lattmann, T., Lüscher, T.F., Shaw, S. Hypertension (2000) [Pubmed]
  5. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Barton, M., Haudenschild, C.C., d'Uscio, L.V., Shaw, S., Münter, K., Lüscher, T.F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism. Mitchell, A., Lückebergfeld, B., Bührmann, S., Rushentsova, U., Nürnberger, J., Siffert, W., Schäfers, R.F., Philipp, T., Wenzel, R.R. Clin. Pharmacol. Ther. (2004) [Pubmed]
  7. Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade. d'Uscio, L.V., Barton, M., Shaw, S., Moreau, P., Lüscher, T.F. Hypertension (1997) [Pubmed]
  8. Transient involvement of endothelin in hypertrophic remodeling of small arteries. Dao, H.H., Martens, F.M., Larivière, R., Yamaguchi, N., Cernacek, P., de Champlain, J., Moreau, P. J. Hypertens. (2001) [Pubmed]
  9. Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension. Quaschning, T., Ruschitzka, F., Niggli, B., Lunt, C.M., Shaw, S., Christ, M., Wehling, M., Lüscher, T.F. Nephrol. Dial. Transplant. (2001) [Pubmed]
  10. Up-regulated inflammatory factors endothelin, NFkappaB, TNFalpha and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats. Xia, H.J., Dai, D.Z., Dai, Y. Life Sci. (2006) [Pubmed]
  11. Effects of chronic hypoxia on renal PDGF-A, PDGF-B, and VEGF gene expression in rats. Schweda, F., Blumberg, F.C., Schweda, A., Nabel, C., Holmer, S.R., Riegger, G.A., Pfeifer, M., Krämer, B.K. Nephron (2000) [Pubmed]
  12. Endothelin receptor antagonists are not beneficial in the therapy of acute experimental pancreatitis. Martignoni, M.E., Ceyhan, G.O., Ayuni, E., Kondo, Y., Zimmermann, A., Büchler, M.W., Friess, H. Langenbeck's archives of surgery / Deutsche Gesellschaft für Chirurgie. (2004) [Pubmed]
  13. Endothelin-1 inhibits the neuronal norepinephrine transporter in hearts of male rats. Backs, J., Bresch, E., Lutz, M., Kristen, A.V., Haass, M. Cardiovasc. Res. (2005) [Pubmed]
  14. LU135252, an endothelin(A) receptor antagonist did not prevent pulmonary vascular remodelling or lung fibrosis in a rat model of myocardial infarction. Nguyen, Q.T., Colombo, F., Rouleau, J.L., Dupuis, J., Calderone, A. Br. J. Pharmacol. (2000) [Pubmed]
  15. Treatment with darusentan over 21 days improved cGMP generation in patients with chronic heart failure. Philipp, S., Monti, J., Pagel, I., Langenickel, T., Notter, T., Ruschitzka, F., Lüscher, T., Dietz, R., Willenbrock, R. Clin. Sci. (2002) [Pubmed]
  16. Effects of the endothelin a receptor antagonist darusentan on blood pressure and vascular contractility in type 2 diabetic Goto-Kakizaki rats. Witte, K., Reitenbach, I., Stolpe, K., Schilling, L., Kirchengast, M., Lemmer, B. J. Cardiovasc. Pharmacol. (2003) [Pubmed]
  17. Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs. Basso, C., Thiene, G., Della Barbera, M., Angelini, A., Kirchengast, M., Iliceto, S. Cardiovasc. Res. (2002) [Pubmed]
  18. Radioreceptor assay of an endothelin A receptor antagonist in plasma and urine. Cernacek, P., Franchi, L., Dupuis, J., Rouleau, J.L., Levy, M. Clin. Chem. (1998) [Pubmed]
  19. Endothelin-1 and thromboxane A2 increase pulmonary vascular resistance in granulocyte-mediated lung injury. Schmeck, J., Janzen, R., Münter, K., Neuhof, H., Koch, T., Janzen, R. Crit. Care Med. (1998) [Pubmed]
  20. Endothelin-A receptor antagonist reduces microcirculatory disturbances and transplant dysfunction after partial liver transplantation. Palmes, D., Budny, T.B., Stratmann, U., Herbst, H., Spiegel, H.U. Liver Transpl. (2003) [Pubmed]
  21. Neurohumoral and hemodynamic effects of the selective endothelin antagonist darusentan in advanced chronic heart failure. Bergler-Klein, J., Pacher, R., Berger, R., Bojic, A., Stanek, B. J. Heart Lung Transplant. (2004) [Pubmed]
  22. Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. d'Uscio, L.V., Moreau, P., Shaw, S., Takase, H., Barton, M., Lüscher, T.F. Hypertension (1997) [Pubmed]
  23. Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. Barton, M., Shaw, S., d'Uscio, L.V., Moreau, P., Lüscher, T.F. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  24. Effects of chronic hypoxia on renal renin gene expression in rats. Schweda, F., Blumberg, F.C., Schweda, A., Kammerl, M., Holmer, S.R., Riegger, G.A., Pfeifer, M., Krämer, B.K. Nephrol. Dial. Transplant. (2000) [Pubmed]
  25. Endothelin ETA receptor blockade with darusentan increases sodium and potassium excretion in aging rats. Traupe, T., Ortmann, J., Haas, E., Münter, K., Parekh, N., Hofmann-Lehmann, R., Baumann, K., Barton, M. J. Cardiovasc. Pharmacol. (2006) [Pubmed]
  26. Profile of past and current clinical trials involving endothelin receptor antagonists: the novel "-sentan" class of drug. Battistini, B., Berthiaume, N., Kelland, N.F., Webb, D.J., Kohan, D.E. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  27. Receptor- and non-receptor-mediated clearance of big-endothelin and endothelin-1: differential effects of acute and chronic ETA receptor blockade. Burkhardt, M., Barton, M., Shaw, S.G. J. Hypertens. (2000) [Pubmed]
  28. Chronic ET(A) receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice. d'Uscio, L.V., Barton, M., Shaw, S., Lüscher, T.F. Cardiovasc. Res. (2002) [Pubmed]
  29. Regression of medial elastocalcinosis in rat aorta: a new vascular function for carbonic anhydrase. Essalihi, R., Dao, H.H., Gilbert, L.A., Bouvet, C., Semerjian, Y., McKee, M.D., Moreau, P. Circulation (2005) [Pubmed]
  30. ET(A) receptor blockade protects the small intestine against ischaemia/reperfusion injury in dogs via an enhancement of antioxidant defences. Andrási, T.B., Kékesi, V., Blázovics, A., Dóbi, I., Szabó, G., Juhász-Nagy, A. Clin. Sci. (2002) [Pubmed]
  31. Improved recovery following posttransplant acute renal failure in rat renal isografts with an oral endothelin-A receptor antagonist. Braun, C., Vetter, S., Conzelmann, T., Schaub, M., Kirchengast, M., van der Woude, F.J., Rohmeiss, P. Exp. Nephrol. (2000) [Pubmed]
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